Summary of work: Hippocampal neurons from the fetal trisomy 16 mouse (Ts16), a model for Down's syndrome (DS, trisomy 21), showed increased high-voltage-activated calcium currents compared with control fetal diploid neurons. The trisomic neurons also bound more L-type calcium ligand. However, NMDA evoked currents did not differ from those in normal diploid neurons. Thus, this trisomic condition selectively affects ionic responses and channels. The effect, if present also in Down syndrome, could have an impact on brain wiring and contribute to mental retardation. As hypotonia is a phenotypic feature of Down's syndrome, which affects motor ability, we investigated electrical properties of the cultured fetal trisomy 16 muscle cells. Two currents involved in repolarization of the action potential were abnormal. Chloride conductance was increased and potassium conductance was decreased compared with control muscle cells. Similar changes, if they occur may explain hypotonia in Down's syndrome. We investigated the phenomenon of long-term potentiation (LTP) in a new genetic model of Down's syndrome, mouse Ts65Dn segmental trisomy. Ts65Dn mice are trisomic only for the part of mouse chromosome 16 that is syntenic with human chromosome 21. These mice, unlike full trisomy 16, survive well into adulthood. Field excitatory postsynaptic potentials were recorded in vitro from the CA1 area of hippocampal slices and LTP was induced by a single tetanizing pulse train 1 s at 100 Hz. LTP was reduced significantly in both 2 mo-old and 9-mo old Ts65Dn hippocampal slices. This finding may explain the reported behavioral and learning impairments in this mouse model as well as in Down's syndrome.